We previously determined the amino acid sequences of human, mouse, rat, and bovine retinal S-antigen and rat pineal gland S-antigen. Immunogenic sites and four uveitopathogenic sites of S-antigen also were determined. Two of the immunogenic sequences were highly conserved among these species. Many proteins in the National Biomedical Research Foundation data base have sequences similar to that of a uveitopathogenic site. We chemically synthesized many peptides, some of which induced experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) in Lewis rats. The peptides include synthetic peptides from yeast (Saccharomyces cerevisiae) histone H3, Escherichia coli hypothetical protein, potato proteinase inhibitor, hepatitis virus protein, Moloney murine sarcoma virus protein, and Moloney murine leukemia virus protein. In addition, native yeast histone H3 was capable of inducing EAU. The animals administered yeast histone by the oral route suppressed the induction of EAU and EAP by either the yeast histone H3 peptide or an S-antigen peptide. Thus, the peptides that have molecular mimicry cross-induced the tolerance. These findings provide a basis for autoimmune inflammatory diseases of the eye in humans. To understand the role in autoimmunity of infectious microorganisms which have cross-reactive antigens, we injected Lewis rats with peptide M together with one of six different killed bacteria, either with or without incomplete Freund's adjuvant (IFA). The rats injected with IFA developed EAU, but most rats injected without IFA did not develop EAU. To assess the impact of infection by live microorganisms, we injected the rats several times with low doses of live E. coli expressing S- antigen and baker's yeast with a cross-reactive antigen. The rats injected with either live E. coli or live yeast developed EAU. We conclude that infection by microorganisms that have cross-reactive antigens can break immune tolerance to self-antigens and induce inflammatory autoimmune diseases.